HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis

Cardiovasc Res. 2012 Jul 1;95(1):116-23. doi: 10.1093/cvr/cvs158. Epub 2012 Apr 30.


Aims: Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis.

Methods and results: Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells.

Conclusion: Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / metabolism*
  • Benzoquinones / pharmacology*
  • Cell Differentiation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Lactams, Macrocyclic / pharmacology*
  • Macrophages / cytology
  • Male
  • Mice
  • Muscle, Smooth, Vascular / drug effects
  • NADPH Oxidases / metabolism
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism


  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Reactive Oxygen Species
  • 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
  • NADPH Oxidases
  • Extracellular Signal-Regulated MAP Kinases